1. Field of the Invention
This invention relates to the field of nutritional supplements and in particular to a chemical composition comprising a stable dry ionic-bonded product bio-engineered from creatine monohydrate and α-ketoglutarate.
2. Description of the Background
Creatine (Cr) is an amino acid derivative (α-methyl guanidine-acetic acid) naturally present in the human body. It is either taken up from food by intestinal absorption or is synthesized endogenously, primarily in kidney, pancreas, and liver. See: creatine and creatine Deficiency Syndromes. 2010 by Elsevier: 163-171. There is a marked separation between the tissues that produce creatine and those that utilize most of it. creatine is distributed throughout the body, 95% found in skeletal muscle, and most of the remaining 5% of the creatine pool is located in brain, liver, kidney, and testis. Brain has an autonomous creatine synthesis pathway, the blood-brain barrier being poorly permeable to creatine. See: Functions and Effects of creatine in the Central Nervous System. 2008 Brain Res Bull; 76: 329-43. Thus the liver-kidney axis for endogenous creatine synthesis is apparently essential for providing creatine to peripheral tissues (including muscle), but to a lesser extend for the brain. A Na+-driven plasma membrane creatine transporter in brain, muscle, heart, and kidney is required for cellular uptake of creatine. See: Extracellular creatine regulates creatine transport in rat and human muscle cells. 1988 Proc. Natl. Acad. Sci USA; 85: 807-11. Circulating creatine is taken up into creatine-requiring tissues by creatine-transporter, which spans the plasma membrane, against a large concentration gradient: plasma [Cr] 50 μmol/L against intracellular [Cr+CP]>40 mmol/L. See: creatine and the creatine transporter: a review 2001. Mol. Cell Biochem; 224: 169-81.
In the cell, creatine is part of the creatine Kinase (CK) system that provides for the Adenosine tri-phosphate (ATP) re-synthesis, which is a key energy source for every metabolic activity. Disturbances of the CK system have been reported in muscle, brain, cardiac and renal malfunctions. On the other hand, creatine was found to have ergogenic, antitumor, antiviral, and anti-diabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, and muscle damage. See: Creatine and Creatinine Metabolism 2000 July; 80 (3): 1107-213. Oral creatine ingestion is popular with athletes who wish to build up muscle, as well as with aging subjects to slow down muscle loss.
The estimated total body pool of total Cr in a 158 Lbs (70 kg) man is about 120 g (See: Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation 1992. Clin. Sci; 83: 367-74). Based on measurements of renal excretion of creatinine (Crn), the daily requirement for Cr from endogenous biosynthesis, is approximately 2 g/day, or 340 μmol/kg/day. This suggests a relatively slow turnover rate of creatine in skeletal muscle with a T1/2 of approximately 26 days (See: Scientific facts behind creatine monohydrate as sport nutrition supplement 1999. J. Sports Med. Phys. Fitness; 39 (3): 179-88).
Given these circumstances, there is an important need in the art for a method to improve the absorption of creatine along with its further expedient delivery to the target tissue and inside the cells. This would allow inter-alia a better control over the dosage/effect dependence for creatine supplementation and overly improve its quality. Previous attempts have focused on improving the digestive absorbability of creatine by enhancing its solubility, but these earlier attempts did not create the desired increased absorbability. See: creatine: 12 Facts Every Consumer Should Know 2005, AAEFX.
α-Ketoglutarate is also a natural compound synthesized in a mammal as part of the Krebs cycle. It has high chemical affinity for nitrogen to reduce nitrogen overload and also for trans-amination, and plays a role in the prevention of ammonia toxicity. As an important intermediate in the Krebs cycle, α-ketoglutarate easily permeates muscle cell membrane and α-ketoglutarate has been a desirable tool to boost muscle energy. Furthermore, α-ketoglutarate is a co-catalyst by undergoing oxygenation alongside oxygenases, to permit oxygenation of various cellular targets. It is often a compound recommended to athletes. In contrast, in the present invention, α-ketoglutarate is utilized because of its remarkably high chemical affinity for nitrogen in general, but, particularly, for the guanidine-functional group from creatine. As described below, we were able to exploit this property of α-ketoglutarate in bioengineering an ionic-bonded creatine α-ketoglutarate vehicle for creatine to deliver the latter to the muscle against a pre-existing high concentration gradient barrier for dietary creatine.
Each of l-Arginine, l-Taurine, and l-Citrulline are often provided for enhancing muscle strength and mass. See: Citrulline/malate promotes aerobic energy production in human exercising muscle 2002. Br J. Sports Med. 36(4):282-9, PMID 12145119. All three are semi-essential or non-essential amino acids formed naturally in the body. L-Arginine is the universal precursor for endogenous creatine and nitric oxide (NO) biosynthesis. See: Argenine: Clinical potential of a semi-essential amino 2002. Altern. Med. Rev. December; 7(6): 512-22. L-Taurine is ultimate sulfur donator for the cystein-cystine redox (antioxidant) system, alongside with glutothione. L-Citrulline, like l-arginine and l-ornithine is a metabolite in the urea cycle and is involved in liver detoxification and vasodilation pathways. Formed from glutamic acid and ornithine in the body, it is added by others to many formulas in an attempt to spare l-arginine for production of NO. See: Citrullin/malate promotes aerobic energy production in human exercising muscle 2002. Br. J. Sports Med. August; 36(4): 282-9. Yet, there is a dramatic difference in the doses of these amino acids used elsewhere, compared to both the dosage and the role of creatine as a bioavailability enhancing factor.